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2.
Front Immunol ; 12: 653950, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833766

RESUMO

Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called "vascular hypothesis" represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an "inflammation-driven pathway to fibrosis". The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33725262

RESUMO

The concern about the offspring's health is one of the reasons for a reduced family size of women with rheumatic diseases (RD). Increased risk of autoimmune diseases (AD) and neurodevelopmental disorders (ND) has been reported in children born to patients with RD. Within a nationwide survey about reproductive issues of women with RD, we aimed at exploring the long-term outcome of their children. By surveying 398 patients who received their diagnosis of RD during childbearing age (before the age of 45), information about the offspring were obtained from 230 women who declared to have had children. A total of 148 (64.3%) patients were affected by connective tissue diseases (CTD) and 82 (35.7%) by chronic arthritis. Data on 299 children (156 males, 52.1%; mean age at the time of interview 17.1 ± 9.7 years) were collected. Twelve children (4.0%), who were born to patients with CTD in 75% of the cases, were affected by AD (8 cases of celiac disease). Eleven children had a certified diagnosis of ND (3.6%; 6 cases of learning disabilities); 9 of them were born to mothers with CTD (5 after maternal diagnosis). No association was found between ND and prenatal exposure to either maternal autoantibodies or anti-rheumatic drugs. Absolute numbers of offspring affected by AD and ND were low in a multicentre cohort of Italian women with RD. This information can be helpful for the counselling about reproductive issues, as the health outcomes of the offspring might not be an issue which discourage women with RD from having children.

7.
Lancet Rheumatol ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33655218

RESUMO

Background: Patients with severe COVID-19 develop a life-threatening hyperinflammatory response to the virus. Interleukin (IL)-1 or IL-6 inhibitors have been used to treat this patient population, but the comparative effectiveness of these different strategies remains undetermined. We aimed to compare IL-1 and IL-6 inhibition in patients admitted to hospital with COVID-19, respiratory insufficiency, and hyperinflammation. Methods: This cohort study included patients admitted to San Raffaele Hospital (Milan, Italy) with COVID-19, respiratory insufficiency, defined as a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of 300 mm Hg or less, and hyperinflammation, defined as serum C-reactive protein concentration of 100 mg/L or more or ferritin concentration of 900 ng/mL or more. The primary endpoint was survival, and the secondary endpoint was a composite of death or mechanical ventilation (adverse clinical outcome). Multivariable Cox regression analysis was used to compare clinical outcomes of patients receiving IL-1 inhibition (anakinra) or IL-6 inhibition (tocilizumab or sarilumab) with those of patients who did not receive interleukin inhibitors, after accounting for baseline differences. All patients received standard care. Interaction tests were used to assess the probability of survival according to C-reactive protein or lactate dehydrogenase concentrations. Findings: Of 392 patients included between Feb 25 and May 20, 2020, 275 did not receive interleukin inhibitors, 62 received the IL-1 inhibitor anakinra, and 55 received an IL-6 inhibitor (29 received tocilizumab and 26 received sarilumab). In the multivariable analysis, compared with patients who did not receive interleukin inhibitors, patients treated with IL-1 inhibition had a significantly reduced mortality risk (hazard ratio [HR] 0·450, 95% CI 0·204-0·990, p=0·047), but those treated with IL-6 inhibition did not (0·900, 0·412-1·966; p=0·79). In the multivariable analysis, there was no difference in adverse clinical outcome risk in patients treated with IL-1 inhibition (HR 0·866, 95% CI 0·482-1·553; p=0·63) or IL-6 inhibition (0·882, 0·452-1·722; p=0·71) relative to patients who did not receive interleukin inhibitors. For increasing C-reactive protein concentrations, patients treated with IL-6 inhibition had a significantly reduced risk of mortality (HR 0·990, 95% CI 0·981-0·999; p=0·031) and adverse clinical outcome (0·987, 0·979-0·995; p=0·0021) compared with patients who did not receive interleukin inhibitors. For decreasing concentrations of serum lactate dehydrogenase, patients treated with an IL-1 inhibitor and patients treated with IL-6 inhibitors had a reduced risk of mortality; increasing concentrations of lactate dehydrogenase in patients receiving either interleukin inhibitor were associated with an increased risk of mortality (HR 1·009, 95% CI 1·003-1·014, p=0·0011 for IL-1 inhibitors and 1·006, 1·001-1·011, p=0·028 for IL-6 inhibitors) and adverse clinical outcome (1·006, 1·002-1·010, p=0·0031 for IL-1 inhibitors and 1·005, 1·001-1·010, p=0·016 for IL-6 inhibitors) compared with patients who did not receive interleukin inhibitors. Interpretation: IL-1 inhibition, but not IL-6 inhibition, was associated with a significant reduction of mortality in patients admitted to hospital with COVID-19, respiratory insufficiency, and hyperinflammation. IL-6 inhibition was effective in a subgroup of patients with markedly high C-reactive protein concentrations, whereas both IL-1 and IL-6 inhibition were effective in patients with low lactate dehydrogenase concentrations. Funding: None.

8.
Clin Exp Rheumatol ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33666154

RESUMO

OBJECTIVES: Biologic drugs (bDMARD), especially TNF-α-inhibitors (TNFi), are used in refractory Takayasu's arteritis (TAK) patients. Up to 23% of patients are switched to a different bDMARD because of inefficacy. No data are available on which strategy is more efficient after TNFi failure. The aim of our study is to evaluate whether a switch or swap strategy should be preferred in TAK patients failing TNFis. METHODS: TAK patients treated with a second bDMARD after the failure of the first TNFi were identified from 3 referral centres. Patients were classified as switch if treated with a different TNFi, and swap if treated with a non-TNFi bDMARD. Baseline features were evaluated. Efficacy and safety of the second bDMARD at 6 and 12 months were assessed and a comparison between switch and swap patients was made. RESULTS: Twenty-four TAK patients were identified. Eleven patients (46%) were switched and 13 patients (54%) were swapped (12 to tocilizumab, 1 to ustekinumab). Baseline features of patients in the 2 groups were comparable. At 12 months, the second bDMARD was suspended in 4 switch (36%) and in 5 swap (42%) patients. Second biologic drug survival and relapse-free survival were equivalent between the two groups at 6 and 12 months. A vascular worsening was observed in 4 switch (40%) and 2 swap (25%) patients. Severe infections, myocardial infarction, ischemic stroke or cancer were recorded in no patient. CONCLUSIONS: Our retrospective study suggests that in first-line TNFi failure TAK patients both switch and swap strategies can be considered suitable approaches.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33580257

RESUMO

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with Systemic Sclerosis (SSc) in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (SRC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared to 7,202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc (85 from the EUSTAR registry), and compared to 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl positivity, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of dermatomyositis, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls.In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous dermatomyositis, calcinosis, and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.

11.
Eur J Intern Med ; 84: 63-67, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33386207

RESUMO

OBJECTIVE: Rituximab is increasingly used in IgG4-related disease (IgG4-RD) but high costs limit its wide off-label administration. European and US regulatory agencies have recently approved rituximab biosimilars for the treatment of different rheumatologic and hematological conditions. No data are available, yet, on the efficacy and safety of rituximab biosimilars for the treatment of IgG4-RD. Scope of the present work is to evaluate the efficacy and safety of the rituximab biosimilar CT-P10 (RTX-B) in patients with IgG4-RD. METHODS: Patients with active IgG4-RD, naïve to rituximab or switched from the originator (RTX-O) to the biosimilar were treated with RTX-B and prospectively followed-up for 18 months. Safety and efficacy were assessed at six months. Relapse rate was assessed at 18 months. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). RESULTS: Thirty-eight patients were included in this study. Thirty-three patients (87%) were naïve to RTX. Five patients (13%) relapsed after RTX-O and were switched to RTX-B. After six months, 21 patients (60%) achieved disease remission. The median serum IgG4 concentration decreased from 1344 to 575 mg/L (p < 0.01), and the median IgG4-RD RI decreased from 7.5 to 0 (p < 0.01). B-cell depletion was observed in all patients. Eight patients (36%) relapsed within 18 months. Side effects related to RTX-B administration were observed in 14 patients (37%). These results are in line with our previous experience with RTX-O. CONCLUSIONS: The (TruximaTM) rituximab biosimilar CT-P10 represents a safe and effective alternative to rituximab originator for the treatment of IgG4-RD.


Assuntos
Antirreumáticos , Medicamentos Biossimilares , Doença Relacionada a Imunoglobulina G4 , Anticorpos Monoclonais Murinos , Estudos de Coortes , Humanos , Estudos Prospectivos , Rituximab , Resultado do Tratamento
14.
Semin Arthritis Rheum ; 51(1): 1-6, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33340821

RESUMO

OBJECTIVES: To assess drug retention rates (DRRs) and reasons for discontinuation of biologic disease-modifying antirheumatic drugs (bDMARDs) in a large monocentric cohort of patients with adult onset Still's disease (AOSD). METHODS: Clinical data of AOSD patients treated with at least one bDMARD and followed up at our Center were retrospectively evaluated. Data about disease duration, number of previous bDMARDs, concomitant treatments, and reasons for therapy discontinuation were collected. Survival curves were examined by the Kaplan-Meier method and compared using a stratified log-rank test. 24-month DRRs were calculated for each bDMARD. Hazard ratio (HR) for previous bDMARD use was evaluated. RESULTS: Forty-two AOSD patients received a total of 79 bDMARD-courses. Anakinra (ANK; n = 41) was the most frequently used bDMARD, followed by tocilizumab (TCZ; n = 21) and Tumor Necrosis Factor inhibitors (TNFi; n = 17). Biologic agents were administered concomitantly with prednisone in all cases (mean dose, 23 ± 18 mg/day) and with csDMARD therapy in 54 (68%) of courses. Thirty-six (46%) treatment courses were discontinued by 24 months. DRRs at 24 months were 62.5% for TCZ, 53.1% for ANK, and 11.8% for TNFi. ANK and TCZ DRRs were similar (p = 0.576), but significantly higher than TNFi (p = 0.015). Previous biologic therapies did not impact DRR (HR 0.73, 95% CI = 0.40 - 1.31, p = 0.288). CONCLUSIONS: In our AOSD study population, 24 months DRRs of TCZ and ANK were similar and significantly higher than the TNFi DRR. Previous use of biologic agents did not affect DRRs.

15.
Microvasc Res ; 133: 104071, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949574

RESUMO

OBJECTIVE: Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients. METHODS: We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered. RESULTS: We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P = .027) and micro-thrombosis (P < .016), sludge flow (P = .001), and pericapillary edema (P < .001), while recovered patients showed a higher prevalence of enlarged capillaries (P < .001), loss of capillaries (P = .002), meandering capillaries (P < .001), and empty dermal papillae (P = .006). CONCLUSION: COVID-19 patients present microvascular abnormalities at NVC. Currently ill and recovered subjects are characterized by a different distribution of elementary capillaroscopic alterations, resembling acute and post-acute microvascular damage. Further studies are needed to assess the clinical relevance of NVC in COVID-19.


Assuntos
/complicações , Capilares/patologia , Angioscopia Microscópica , Unhas/irrigação sanguínea , Doenças Vasculares/patologia , Idoso , /terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doenças Vasculares/etiologia
16.
Clin Exp Rheumatol ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33337991

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune disease with distinct subsets identified by specific autoantibodies. Some environmental agents might play a role in SSc pathogenesis, including silicone breast implants (SBI). This association has been controversial in previous literature and only few studies reported the auto-antibody status in these SSc women. The objective of this study was to evaluate the association of SBI with SSc in a large cohort of Italian patients, classified according to their SSc-related autoantibodies and to their history of breast cancer. METHODS: Three Italian referral centres retrospectively collected clinical and laboratory data of consecutive SSc women, that were included when fulfilling the 2013 ACR/EULAR criteria and when SSc specific auto-antibodies status was available (anti-centromere (ACA), anti-Topoisomerase I (anti-Topo I) and anti-RNA Polymerase III antibodies (anti-RNAP3)). Data regarding history of SBI, SBI rupture and breast cancer were recorded. RESULTS: Among 742 SSc women, a history of SBI was recorded in 12 patients (1.6%); in only 1 case the implantation occurred before SSc diagnosis. In SSc patients with anti- RNAP3+ a significantly higher frequency of SBI rupture and SBI rupture without breast cancer were observed, as compared to anti-RNAP3-negative patients. No association was noted for SBI without rupture. CONCLUSIONS: In this study we demonstrated a link between SBI rupture and induction of anti-RNAP3+ SSc; further studies are needed to better define the characteristics of this syndrome and the possible effects of SBI removal and immunosuppressive treatment.

19.
J Am Coll Cardiol ; 76(14): 1644-1656, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33004129

RESUMO

BACKGROUND: Little is known about the risk stratification of patients with myocarditis undergoing ventricular tachycardia (VT) ablation. OBJECTIVES: This study sought to describe VT ablation results and identify factors associated with arrhythmia recurrences in a cohort of patients with myocarditis. METHODS: The authors enrolled 125 consecutive patients with myocarditis, undergoing VT ablation. Before ablation, disease stage was evaluated, to identify active (AM) versus previous myocarditis (PM). The primary study endpoint was assessment of VT recurrences by 12-month follow-up. Predictors of VT recurrences were retrospectively identified. RESULTS: All patients (age 51 ± 14 years, 91% men, left ventricular ejection fraction 52% ± 9%) had history of myocarditis diagnosed by endomyocardial biopsy (59%) and/or cardiac magnetic resonance (90%). Furthermore, all had multiple episodes of drug-refractory VTs. Multimodal pre-procedural staging identified 47 patients with AM (38%) and 78 patients with PM (62%). All patients showed low-voltage areas (LVA) at electroanatomical map (97% epicardial or endoepicardial); of them, 25 (20%) had wide borderzone (WBZ, constituting >50% of the whole LVA). VT recurrences were documented in 25 patients (20%) by 12 months, and in 43 (34%) by last follow-up (median 63 months; interquartile range: 39 to 87). At multivariable analysis, AM stage was the only predictor of VT recurrences by 12 months (hazard ratio: 9.5; 95% confidence interval: 2.6 to 35.3; p < 0.001), whereas both AM stage and WBZ were associated with arrhythmia recurrences anytime during follow-up. No VT episodes were found after redo ablation was performed in 23 patients during PM stage. CONCLUSION: Our findings suggest that VT ablation should be avoided during AM, but is often of benefit for recurrent VT after the acute phase of myocarditis.

20.
Expert Opin Drug Saf ; 19(12): 1549-1558, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33078630

RESUMO

INTRODUCTION: Adult onset Still disease (AOSD) is a rare systemic inflammatory condition. The clinical spectrum of this disease ranges from self-limiting forms with mild symptoms to life-threatening cases. Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) represent the first line of therapy for AOSD, with add-on therapy with second-line drug reserved to steroid-dependent patients and in life-threatening cases. Currently, early treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) and biologic agents blocking causal cytokines is advocated in patients with severe and recalcitrant clinical manifestations. AREAS COVERED: This review analyzes the available controlled evidence and observational data regarding the efficacy and safety of conventional and biological pharmacological agents in the treatment of AOSD. EXPERT OPINION: Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are effective in controlling clinical manifestations in the majority of AOSD patients. Conventional DMARDs can be 20 effective in some severe and steroid-dependent cases of AOSD; however, anti-cytokine agents represent an effective and overall more suitable alternative in this specific subset of patients. IL-1 and IL-6 blockade are effective in treating systemic and articular inflammation of AOSD patients. IL-1 blockade also has an excellent safety profile and therefore represent the first choice of biologic treatment in this clinical scenario.

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